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OBJECTIVE: As a key member of transient receptor potential (TRP) superfamily, TRP canonical 3 (TRPC3) regulates calcium homeostasis and contributes to neuronal excitability. Ablation of TRPC3 lessens pilocarpine-induced seizures in mice, suggesting that TRPC3 inhibition might represent a novel antiseizure strategy. Among current TRPC3 inhibitors, pyrazole 3 (Pyr3) is most selective and potent. However, Pyr3 merely provides limited benefits in pilocarpine-treated mice likely due to its low metabolic stability and potential toxicity. We recently reported a modified pyrazole compound 20 (or JW-65) that has improved stability and safety. The objective of this study was to explore the effects of TRPC3 inhibition by our current lead compound JW-65 on seizure susceptibility. METHODS: We first examined the pharmacokinetic properties including plasma half-life and brain to plasma ratio of JW-65 after systemic administration in mice. We then investigated the effects of TRPC3 inhibition by JW-65 on behavioral and electrographic seizures in mice treated with pilocarpine. To ensure our findings are not model specific, we assessed the susceptibility of JW-65-treated mice to pentylenetetrazole (PTZ)-induced seizures with phenytoin as a comparator. RESULTS: JW-65 showed adequate half-life and brain penetration in mice, justifying its uses for CNS conditions. Systemic treatment with JW-65 before pilocarpine injection in mice markedly impaired the initiation of behavioral seizures. This antiseizure action was recapitulated when JW-65 was administered after pilocarpine-induced behavioral seizures were well established and was confirmed by time-locked electroencephalography (EEG) monitoring and synchronized video. Moreover, JW-65-treated mice showed substantially decreased susceptibility to PTZ-induced seizures in a dose-dependent manner. SIGNIFICANCE: These results suggest that pharmacological inhibition of the TRPC3 channels by our novel compound JW-65 might represent a new antiseizure strategy engaging a previously undrugged mechanism of action. Hence, this proof-of-concept study establishes the TRPC3 as a novel feasible therapeutic target for the treatment of some forms of epilepsy.

Diabetes is a disease that affects over 150 million people worldwide for which there are multiple oral and injectable medications. Because of trends in obesity and sedentary lifestyles, diabetes rates in both developed and developing countries are increasing at an alarming rate. Current medications are not adequately effective in maintaining long-term glycemic control in most patients, even when used in combination, leaving diabetics susceptible to developing life threatening and debilitating complications such as cardiovascular disease, blindness, kidney complications, and amputations. Consequently, there is a critical need for more potent pharmacotherapies with novel mechanisms of action. A panel of 20 emerging diabetes targets is presented, and small molecule modulators for each target will be discussed.

New boronated unnatural cyclic amino acids, 1–6, were synthesized for potential use in neutron capture therapy. In order to understand the effect of molecular lipophilicity on the biological activity, different linkers were introduced between the boronic acid and 1-aminocycloalkanecarboxylic acid moieties. The key step in the syntheses was the preparation of a series of alkenyl-substituted cycloalkanones, which were subsequently converted to amino acids via the Bucherer–Strecker reaction. The introduction of the boronic acid function into hydrantoins 19–24 was realized by hydroboration reactions using diisopinocampheylborane (Ipc2BH). The target boronated amino acids were modeled after 1-aminocyclobutanecarboxylic acid and 1-amino-3-boronocyclopentanecarboxylic acid, which have previously demonstrated high uptake in tumors. Copyright © 2008 John Wiley & Sons, Ltd.

Dialkynylboron chlorides couple smoothly with aryl aldehydes at room temperature to afford 1,4-dialkynes in good to excellent yields. Dialkynylboron halides act simultaneously as Lewis acid and reactant in this coupling reaction.

Aryl aldehydes react with alkylboron chloride derivatives in the presence of base to generate the corresponding arylalkylmethanols in good yields. A variety of alkylboron chlorides can be utilized in the new alkylation reaction.

The chlorination of aromatic aldehydes with boron trichloride in hexane under reflux conditions produces the corresponding dichloromethyl derivatives in excellent yields.

The reductive bromination of aromatic aldehydes with isopinocampheyl boron dibromide in hexane at room temperature produces the corresponding benzyl bromides in excellent yields.

The reaction of aryl aldehydes with alkylboron chlorides has been investigated. Monoalkylboron dichlorides react with aryl aldehydes in hexane under reflux conditions to give a mixture of dichloroarylmethane and benzyl chloride. Under the same reaction conditions, dialkylboron chlorides lead to formation of a mixture of benzyl chloride and the chloroalkylation product. In the presence of a base such as 2,6-lutidine, the reactions of monoalkylboron dichlorides with aryl aldehydes yield small amounts of the desired alkylation products at room temperature. Dialkylboron chlorides react with aryl aldehydes in hexane in the presence of base to generate the corresponding arylalkylmethanols in good yields.

Stilbenes are readily prepared in good yields via homocoupling of aryl aldehyde tosylhydrazones in the presence of lithium tert -butoxide and trimethyl borate under reflux in THF.

Reactions of aryl aldehydes with alkylboron dichlorides in the presence of oxygen at room temperature produces arylalkyl chlorides in good to excellent yields.

Reactions of aryl aldehydes with styrenes in the presence of boron trichloride in CH2Cl2 at 0°C produce 1,3-dichloro-1,3-diarylpropanes in excellent yields. Reactions carried out using boron tribromide generate the corresponding 1,3-dibromo-1,3-diarylpropane in good yields.

The reactions of aryl aldehydes with 2 equiv of arylacetylenes in the presence of boron trichloride yield (E,Z)-1,3,5-triaryl-1,5-dichloro-1,4-pentadienes. Reactions carried out in the presence of ...

Reactions of aromatic aldehydes with alkylboron chloride derivatives in the presence of oxygen have been investigated. Dialkylboron chlorides react with aryl aldehydes to produce arylalkylmethanols in good to excellent yields. Under the same reaction conditions, alkylboron dichlorides lead to the formation of arylalkyl chlorides.

Alkoxide C−O bond cleavage occurs readily at room temperature in the presence of titanium(IV) halide. Capture of the resultant carbocation by alkynes provides an efficient route to trisubstituted (E)-alkenyl halides with high stereoselectivity.

Diabetes is a disease that affects over 150 million people worldwide for which there are multiple oral and injectable medications. Because of trends in obesity and sedentary lifestyles, diabetes rates in both developed and developing countries are increasing at an alarming rate. Current medications are not adequately effective in maintaining long-term glycemic control in most patients, even when used in combination, leaving diabetics susceptible to developing life threatening and debilitating complications such as cardiovascular disease, blindness, kidney complications, and amputations. Consequently, there is a critical need for more potent pharmacotherapies with novel mechanisms of action. A panel of 20 emerging diabetes targets is presented, and small molecule modulators for each target will be discussed.

A direct hydroboration of alkene-containing hydantoins using diisopinocampheylborane has been developed that can be used to prepare boronated amino acids. The method is successful because boronic acids are stable to the conditions employed for hydrolyzing hydantoins.

[reaction: see text] Substitution of benzylic hydroxyl groups with vinyl moieties using vinylboron dihalides has been achieved. The reaction provides a novel method for preparing stereodefined alkenyl halides.

Organoboron chlorides and bromides are valuable reagents for halogenation and alkylation of aromatic aldehydes, addition of aldehydes to alkenes, and dialkenylation of aldehydes. An overview of these newly discovered reactions is presented.

A novel two-step aldehyde homologation procedure for the preparation of methyl ketones has been developed, which involves the use of 1,1-dibromo-1-alkenes as precursors and zinc metal as mediator in near-critical water.